Elena I. Varlinskaya

Motivational Systems in Adolescence: Possible Implications for Age Differences in Substance Abuse and Other Risk-Taking Behaviors.

Adolescence is an evolutionarily conserved developmental phase characterized by hormonal, physiological, neural and behavioral alterations evident widely across mammalian species. For instance, adolescent rats, like their human counterparts, exhibit elevations in peer-directed social interactions, risk-taking/novelty seeking and drug and alcohol use relative to adults, along with notable changes in motivational and reward-related brain regions. After reviewing these topics, the present paper discusses conditioned preference and aversion data showing adolescents to be more sensitive than adults to positive rewarding properties of various drugs and natural stimuli, while less sensitive to the aversive properties of these stimuli. Additional experiments designed to parse specific components of reward-related processing using natural rewards have yielded more mixed findings, with reports of accentuated positive hedonic sensitivity during adolescence contrasting with studies showing less positive hedonic affect and reduced incentive salience at this age. Implications of these findings for adolescent substance abuse will be discussed.

Nicotine-induced conditioned place preference in adolescent and adult rats

About 1 million American adolescents start smoking every year. Adolescents may be unusually sensitive to certain consequences of nicotine, demonstrating, for instance, significantly higher rates of dependence than adults at the same level of nicotine use. To explore whether adolescents may be more sensitive to rewarding properties of nicotine than adults, the present study used an animal model to assess the rewarding effects of a low nicotine dose (0.6 mg/kg) in a conditioned place preference (CPP) paradigm. Locomotor activity during conditioning and testing was also evaluated. Nicotine was observed to induce place preference conditioning in adolescent Sprague-Dawley rats, whereas the training dose of 0.6 mg/kg failed to produce convincing place preference in their adult counterparts. Age differences were also apparent in terms of nicotine influences on motor activity, with adults being more sensitive to nicotine-suppressant effects and only adolescents showing an emergence of nicotine-stimulatory effects upon repeated exposures. An increased predisposition to stimulatory nicotine effects during adolescence may contribute to age-specific rewarding properties of the drug as revealed using the CPP paradigm in this experiment. Increased sensitivity to stimulatory and rewarding effects during adolescence could potentially contribute to the high rate of nicotine use and dependence among human adolescents.

Anxiogenic effects during withdrawal from acute ethanol in adolescent and adult rats

Elevated signs of anxiety are observed in adult rodents during withdrawal from chronic as well as acute ethanol exposure. To determine whether adolescents, in addition to their insensitivity to a number of acute ethanol effects, might likewise be hyposensitive to these anxiogenic manifestations of withdrawal from an acute ethanol challenge, the behavior of adolescent and adult male Sprague-Dawley rats was assessed in an elevated plus maze (EPM) 18 h following intraperitoneal challenge with 4 g/kg ethanol. Adult but not adolescent animals demonstrated evidence of anxiety in the plus maze during acute ethanol withdrawal. To ensure that this finding did not merely reflect age differences in ethanol clearance, clearance times at each age were determined, with additional adolescents tested at the same time postclearance as the adults were previously. Adolescents still failed to demonstrate anxiogenic signs of withdrawal. Suppression of activity during the withdrawal test, however, was evident in animals of both ages. A relative resistance to the anxiogenic effects associated with acute ethanol withdrawal during adolescence could serve as a permissive factor for development of binge drinking patterns among human adolescents.

Social Behavior and Social Motivation in Adolescent Rats: Role of Housing Conditions and Partner's Activity

The present study investigated 1) the effects of individual and grouped housing on social investigation, social contact behavior, and play behavior in adolescent rats tested with low socially active (grouped) and high socially active (isolated) play partners; and 2) the effects of long-term (8 days) and short-term (24 h) isolation on social behavioral manifestations and social motivation in terms of preference or avoidance of play partners. Social isolation of adolescent rats activated play behavior and social behaviors different from play, but play was predominantly affected under the conditions of this study. Long-term isolation was more effective than short-term, and resulted in greater manifestation of play and social preference. Adolescent rats were able to modify their social behaviors in response to social activity of the play partner: in isolated animals exposed to low socially active group-housed partners, play behavior was transformed into social activities unrelated to play; exposure of group-housed adolescents to high socially active previously isolated partners resulted in an increase of play behavior. Testing that allowed avoidance of social contacts revealed a dissociation between manifestations of play behavior and social motivation: group-housed play partners of isolated animals showed elevated levels of play behavior but a tendency to avoid their isolated pairmates.

Social and non-social anxiety in adolescent and adult rats after repeated restraint

Adolescence is associated with potentially stressful challenges, and adolescents may differ from adults in their stress responsivity. To investigate possible age-related differences in stress responsiveness, the consequences of repeated restraint stress (90 min/day for 5 days) on anxiety, as indexed using the elevated plus-maze (EPM) and modified social interaction (SI) tests, were assessed in adolescent and adult Sprague-Dawley male and female rats. Control groups at each age included non-stressed and socially deprived animals, with plasma corticosterone (CORT) levels also measured in another group of rats on days 1 and 5 of stress (sampled 0, 30, 60, 90, and 120 min following restraint onset). While repeatedly restrained animals exhibited similar anxiety levels compared to non-stressed controls in the EPM, restraint stress increased anxiety at both ages in the SI test (as indexed by reduced social investigation and social preference). Daily weight gain measurements, however, revealed more marked stress-related suppression of body weight in adolescents versus adults. Analysis of stress-induced increases in CORT likewise showed that adolescents demonstrated less habituation than adults, embedded within typical sex differences in CORT magnitude (females greater than males) and age differences in CORT recovery (adolescents slower than adults). Despite no observable age-related differences in the behavioral response to restraint, adolescents were more sensitive to the repeated stressor in terms of physiological indices of attenuated weight gain and habituation of stress-induced CORT.

Social interactions in adolescent and adult Sprague–Dawley rats: Impact of social deprivation and test context familiarity

Interactions with peers become particularly important during adolescence, and age differences in social interactions have been successfully modeled in rats. To determine the impact of social deprivation on social interactions under anxiogenic (unfamiliar) or non-anxiogenic (familiar) test circumstances during ontogeny, the present study used a modified social interaction test to assess the effects of 5 days of social isolation or group housing on different components of social behavior in early [postnatal day (P) 28], mid (P35), or late (P42) adolescent and adult (P70) male and female Sprague-Dawley rats. As expected, testing in an unfamiliar environment suppressed social interactions regardless of age, housing, and sex. Social deprivation drastically enhanced all forms of social behavior in P28 animals regardless of test situation, whereas depriving older animals of social interactions had more modest effects and was restricted predominantly to play fighting -- an adolescent-characteristic form of social interactions. Social investigation -- more adult-typical form of social behavior was relatively resistant to isolation-induced enhancement and was elevated in early adolescent isolates only. These findings confirm that different forms of social behavior are differentially sensitive to social deprivation across ontogeny.

Sex Differences in Ethanol Intake and Sensitivity to Aversive Effects during Adolescence and Adulthood

Aims: The present experiments examined sex differences in ethanol intake and in the influence of a social context on aversive properties of ethanol in adolescent and adult Sprague-Dawley rats. Methods: Experiment 1 examined ethanol intake, with animals receiving daily 2-h access to ethanol and water for 8 days. Experiment 2 assessed the aversive effects of ethanol using a conditioned taste aversion (CTA) paradigm, with animals placed either alone or with a same-sex, same-age peer during the ethanol intoxication phase of conditioning. Results: Ethanol intake varied with both age and sex, although the sex differences emerging at each age were opposite in nature. Adolescent males consumed more ethanol relative to their body weights than adolescent females and adults of both sexes, whereas adult females generally consumed more than adult males. The CTA test revealed no sex differences in aversive effects of ethanol in adults, whereas adolescent males were less sensitive to the aversive properties of ethanol than adolescent females when intoxication occurred in the presence of a peer. Ethanol-induced CTA was evident in adults at lower doses than in adolescents. Conclusions: These results suggest that age differences in ethanol intake in males and sex differences in intake during adolescence may be associated in part with the relative insensitivity of the male adolescents to ethanols aversive properties, especially when intoxication occurred in a social context. However, the elevated ethanol intake observed in adult females relative to their male counterparts appears to be unrelated to the aversive properties of ethanol.

Acute Ethanol Withdrawal (Hangover) and Social Behavior in Adolescent and Adult Male and Female Sprague-Dawley Rats

BACKGROUND The extensive use of alcohol during adolescence may be facilitated by an age-specific attenuation in sensitivity to adverse effects of ethanol. Adolescent rats are less sensitive than adults to some delayed effects of acute ethanol, including hangover-related anxiety on an elevated plus maze. The purpose of this study was to determine whether adolescent rats are also less sensitive than adults to hangover-related anxiogenesis when indexed in terms of social inhibition. METHODS Anxiety during ethanol hangover was indexed in adolescent and adult Sprague-Dawley rats of both genders by assessing the suppression in social behavior during a social interaction test. Animals were tested 18 hr after intraperitoneal administration of 0 g/kg (saline) or 4 g/kg ethanol (experiment 1) or at test intervals chosen on the basis of assessments of ethanol clearance time (experiment 2) to equate clearance-to-test intervals across age and gender (experiments 3-5). RESULTS Adults showed more hangover-related social suppression and slower postclearance recovery than adolescents. Sex differences were more pronounced in adults than adolescents, with males being more affected than females. Ethanol clearance time was considerably longer in adult males than in adolescent animals and adult females. In contrast to the modest decreases in social activity observed in adolescent animals shortly after ethanol clearance, adolescents showed a surprising increase in play fighting later in the recovery period- a hangover-related social facilitation that was not evident in adults. CONCLUSIONS The attenuated anxiety and increase in social interactions seen in adolescents during hangover are less likely to serve as deterrents for further drinking than the aversive increase in anxiety seen in adults. A facilitation of social interactions not only during a drinking episode, but also during the postalcohol recovery period, could help to establish a persisting cycle of drinking in at-risk adolescents, leading to dependency and a lifelong history of alcohol-related problems.

Novel-object place conditioning in adolescent and adult male and female rats: effects of social isolation.

Elevated levels of novelty seeking are often seen during adolescence. Recent studies using a conditioned place preference (CPP) paradigm have shown that novelty may be rewarding for adult rats. The present study explored the impact of age, sex, and isolation stress on novelty seeking and novelty reward by assessing novel object-induced CPP in adolescent and adult male and female Sprague-Dawley rats housed either socially or in isolation. Responding to the novel objects during conditioning was higher in adolescent animals than adults, and was suppressed by social isolation only in adulthood, particularly among males. Novel object CPP was strong among adolescent males, whereas only socially isolated adult males demonstrated preference for the compartment paired with the novel objects. This age difference was not evident in females, with both adolescent and adult group-housed females, but not their isolated counterparts, showing novel-object place conditioning. These dissociations between novelty-directed behaviors during conditioning and novelty reward in the CPP paradigm support the suggestion that mechanisms underlying novelty seeking are separable from those involved in the rewarding effects of novelty. High levels of novelty seeking demonstrated by adolescents do not necessarily predict high rewarding properties of novelty, with the latter also being influenced by environmental and gender-related factors.

Sensitivity to Ethanol and Other Hedonic Stimuli in an Animal Model of Adolescence: Implications for Prevention Science?

Age-related patterns of sensitivity to appetitive and aversive stimuli seemingly have deep evolutionary roots, with marked developmental transformations seen during adolescence in a number of relatively ancient brain systems critical for motivating and directing reward-related behaviors. Using a simple animal model of adolescence in the rat, adolescents have been shown to be more sensitive than their adult counterparts to positive rewarding effects of alcohol, other drugs, and certain natural stimuli, while being less sensitive to the aversive properties of such stimuli. Adolescent-typical alcohol sensitivities may be exacerbated further by a history of prior stress or alcohol exposure as well as by genetic vulnerabilities, permitting relatively high levels of adolescent alcohol use and perhaps an increased probability for the emergence of abuse disorders. A number of potential (albeit tentative) implications of these basic research findings for prevention science are considered.